Overall objectives are to define the clinical pharmacokinetics of heparin including its dose-dependent and time-dependent pharmacokinetics, and its pharmacodynamics. A major effort will be devoted to identifying possible determinants of the anticoagulant effect of heparin and its time course. Previous studies conducted under this grant have demonstrated (1) that the pharmacokinetics of heparin in normal subjects are characterized by a dose-dependent increase in biological half-life, which is the consequence of a dose-dependent decrease in total clearance. No dose-dependent changes were observed in the apparent volume of distribution of heparin; and (2) that the pharmacokinetics of heparin vary markedly depending on which assay method for plasma heparin is used. The most significant difference is that both total clearance and apparent volume of distribution are about 1.5-2.0 times larger when heparin is determined by a chemical neutralization assay than when based on coagulation tests. These studies will be extended to patients, where heparin pharmacokinetics will be defined with respect to dose and time using the same different assay methods. Other studies carried out under this grant have demonstrated that the anticoagulant response to heparin in vitro is determined by baseline coagulation status, i.e., the shorter the APTT of a plasma sample the less sensitive it is to heparin, and vice versa. Concentration of antithrombin III were not found to be a determinant of either baseline coagulation status or response to heparin. Studies are now in progress to develop clinically applicable methodology to determine if the extent of carboxylation of vitamin K dependent clotting factors determines baseline coagulation status and the response to heparin.